U.S. Pat. No. 5,610,294 discloses cyclic urea compounds of formula (X) which are useful as HIV protease inhibitor compounds. ##STR2##
U.S. Pat. No. 5,532,357 discloses methods for the preparation of compounds of formula (X), for example compound (X-a) via the isourea intermediate (XX). ##STR3##
The isourea, (XX), can be used to prepare compounds of formula (X) which are unsymmetrical cyclic ureas.
A key intermediate in the synthesis of cyclic urea HIV protease inhibitors, such as (X-a), is the symmetrical diamine (I) (L. Rossano et al Tetrahedron. Lett., 1995, 36, 4967-4970). ##STR4##
Methodology has been developed that allows for mono acylation of (I) enabling manipulation to unsymmetrical compounds such as (X-a). This mono acylation allows for the synthesis of unsymmetrical cyclic ureas by differentiating the symmetrical amines in (I). Additionally, mono acyl (I) can be prepared by first bis acylation of (I) followed by a selective hydrolysis to the same mono acyl derivative of (I).
T. Blacklock et al (J. Org. Chem, 1988, 53, 836-844) disclose the regioselective trifluoroacylation of L-lysine with ethyl trifluoroacetate in an aqueous sodium hydroxide medium using pH control to cause selective acylation. T. Shawe et al (Synthetic Communications, 1996, 26, 3633-3636) disclose the regiospecific trifluoroacyclation of N-methylethylenediamine by reaction with ethyl trifluoroacetate; although this chemistry uses ethyl trifluoroacetate as the acylating agent, it is distinguishing a primary amine over a secondary amine where one would expect there to be a difference in reactivity between the amines based on steric arguments. These references teach acylation of diamino compounds wherein the diamines are non equivalent sterically and chemically.
D Xu et al (Tetrahedron Letters, 1995, 36, 7357-7360) disclose the mono-trifluoro acylation of diamines, wherein acylation occurs rapidly with one equivalent of acylating agent in a polar solvent such as tetrahydrofuran at or below 0.degree. C. The authors describe mono acylation of a primary amine in a 1,2 diamine system wherein one amine acts as an internal base to activate the other amine. However, in the case of trans 1,2 diaminocyclohexane, a statistical mixture of diamine, mono-acylated and di-acylated material is obtained, indicating that no selectivity has occured. The authors postulate that this result is because one amine is not in close proximity to the other and so cannot promote acylation. Furthermore, the authors teach as the chain length between the amines increases, the degree of selectivity observed decreases.
The process of the present invention should not be amenable to selective acylation following the teachings of the literature, In the stereochemical configuration of diamine (I), the two primary amines have a trans configuration. Additionally, the diamines have a 1,4 relationship and thus there is an increase in the chain length between the amines. In addition, titration of (I) against hydrochloric acid reveals one inflection after two equivalents of acid have been added; because there is only one equivalence point, the two primary amines in (I) are not `communicating` with each other thus one amine cannot be acting as an internal base. Lastly, the two primary amines in (I) are not differentiated sterically.
Experimentally, following the teachings of the literature, in the process of the invention the acylation of diamine (I) results in very little selectivity. The selective trifluoroacylation of (I) occurs with an excess of ethyl trifluoroacetate in a non-polar solvent such as toluene at elevated temperatures; the use of polar solvents, such as tetrahydrofuran, tend to degrade the selectivity.
Despite the various methods for their preparation, there still exists a need for more efficient and cost effective methods for the preparation of unsymmetrical N,N'-disubstututed cyclic urea HIV protease inhibitor compounds in high yield. The present invention provides improved processes for the synthesis of such compounds and processes for the synthesis of intermediates for their synthesis.
The diamine (I) is a key intermediate in the synthesis of unsymmetrical cyclic ureas that can be used as HIV protease inhibitors. This process allows the differentiation of the symmetrical primary amines in diamines of formula (I) in high yield. This process is suitable for large scale and is very volume efficient, providing excellent reactor through put in high yield and with low cost. The intermediates of the invention can be alkylated to give a wide range of unsymmetrical products which are useful as HIV protease inhibitors for the treatment of HIV infection. The dialkylated diamine intermediates of the invention provide starting materials, generally crystalline, suitable for large scale cyclization to cyclic ureas, which are, generally, crystalline.
The present invention provides an improved process for the cyclization of linear dialkylated diamines to cyclic ureas. Deleterious conditions of known processes are presented by an acid rearrangement mechanism, production to a high degree of byproduct, and the unsymmetrical amines of the substrate molecule. The present invention, through use of acid-base salt precipitates, unexpectedly improves upon the process by avoiding the acid rearrangement and minimizing the byproduct; therefore, resulting in a higher yield of cyclized urea in a process more suitable for large scale cyclization.